This invention pertains to a compound which improves oxygen diffusivity from red blood cells to body tissues in mammals, including humans, methods of preparation, and methods of use thereof. Specifically, trans-sodium crocetinate (TSC herein) has been demonstrated to increase oxygen diffusivity, improve oxygen uptake, and is indicated for pharmaceutical utility in a wide variety of applications.
BACKGROUND OF THE PRIOR ART
Human metabolism requires that oxygen be supplied continuously to muscles, organs and various body tissues. Under normal conditions, sufficient oxygen is provided by the atmosphere to sustain life. The oxygen must be transferred to the body tissues in order to be used. The transfer pathway begins with transfer to the blood stream via the lungs, followed by transport as part of the Heme complex to various parts of the body, and finally, passing from the red blood cells to the various tissues. Thus, passage of the oxygen through the alveolar membranes of the lungs, the walls of the blood vessels, the blood plasma itself, red blood cell membranes and the interior of the tissues all provide barriers to oxygen transfer. The movement of oxygen across each barrier is "driven" by a concentration ingredient. If changes occur to that driving force, or to any of the resistances, the amount of oxygen reaching the tissue changes.
A wide variety of conditions, notably among them hemorrhagic shock, are controlled or be mediated by delivery of oxygen to body tissues. It has long been known that "oxygen delivery" to tissues is impacted by the oxygen concentration in the blood, as well as the rate at which blood is flowing. Repeatedly, however, there has been evidence suggesting that these two factors, generally referred to as "oxygen delivery" do not determine the total amount of oxygen consumed. Among other causative agents, the barriers described above pose potential problems. While the resistance of cell membranes to oxygen diffusion appears to be negligible, Wagner et al., J. Applied Physiol., 33:62-71 (1972) and Kreuzer et al., J. Applied Physiol., 15:1117-1122 (1960) there are indications that blood plasma offers a major barrier to oxygen consumption by the tissues. See, e.g., Huxley et al., J. Physiol., 316:75-83 (1981) and Holland et al., Resp. Physiol., 59:71-91 (1985). The inventor herein demonstrated that oxygen diffusivity can be improved, in mammalian models, by administration of the naturally-occurring carotenoid crocetin to the blood volume. Thus, improvements in oxygen diffusivity, oxygen consumption, and survival in rats with induced hemorrhagic shock was demonstrated by the inventor, Gainer et al., Circulatory Shock 41:1-7 (1993). An examination of oxygen uptake by stimulated muscles, and the effect of oxygen diffusivity and related parameters appears in Gainer, J. Applied Physiol. 76:1826-1829 (1994). The discovery that crocetin improves oxygen diffusivity, and the conditions treatable therewith, form the basis of a variety of patents related to the treatment of various conditions based on the use of crocetin. Included in this group are: U.S. Pat. Nos. 4,176,179; 4,070,460; 4,046,880; 4,038,144; 4,009,270; 3,975,519; 3,965,261; 3,853,993 and 3,788,468, largely by the inventor herein, directed to treating conditions including atherosclerosis, treatment of papillomas, treatment of spinal cord injuries, treatment of hypertension, and treatment of cerebral edema.
Notwithstanding these discoveries, certain obstacles remain to the large scale implantation of crocetin as a pharmaceutical for enhancing blood diffusivity in mammals, including humans. One problem is the preparation of the active agent in sufficiently pure and large amounts. Another, more serious problem is the fact that crocetin is nearly insoluble in aqueous solutions, making preparation of a drug for intravenous administration particularly difficult. Finally, reaching and maintaining adequate levels of crocetin to improve oxygen diffusivity, over a length of time, proves difficult.
Thus, is a goal of those of ordinary skill in the art to find a pharmaceutically acceptable drug which can be used to increase, over a sustained period, improvements in oxygen diffusivity, and thus oxygen uptake by the body tissues, in mammals.